PROJECT SUMMARY Sjgren's syndrome is a chronic autoimmune disease characterized by immune cell infiltration into exocrine glands, particularly the salivary and lacrimal glands which leads to severe loss of secretory function and consequent oral and ocular health problems. The disease affects four million Americans with over 90% of those affected being female. Currently, there are no effective therapies to inhibit or reverse the course of Sjgren's syndrome. Treatments are limited to ameliorating the disease's symptoms and may be needed life-long. Accordingly, there is a need to develop new therapeutic approaches for Sjgren's syndrome that can safely control the underlying inflammatory responses. Recently, it has become appreciated that T cells and antigen- presenting cells express gamma-amino-butyric acid receptors (GABA-Rs) and that the activation of these receptors has several desirable effects for inhibiting inflammation, including 1) inhibiting Th17 and Th1 responses, 2) reducing APC proinflammatory activity, and 3) promoting CD4+ and CD8+ Treg responses. These immunoregulatory actions have enabled oral GABA administration to reverse chronic T cell-mediated autoimmune diseases such as type 1 diabetes (T1D), multiple sclerosis (MS), and rheumatoid arthritis after the onset of clinical symptoms in mouse models of these disorders. Human T cells also express GABA-Rs, and GABA has been shown to regulate them in a similar fashion. GABA's immunomodulatory effects are modest, do not cause immuno-depletion, and GABA is safe for human consumption. Clinical trials of oral GABA for T1D are currently underway. Given the ability of GABA-R agonists to reverse disease in different chronic autoimmune disease models, each of which have different etiologies and occur in mice with different genetic backgrounds, it is reasonable to posit that oral GABA treatment could provide a novel and safe therapy to help ameliorate Sjgren's syndrome. This proposal will test the ability of oral GABA therapy to ameliorate disease in two different mouse models of Sjgren's syndrome when given at early and advanced stages of the disease. A proof-of- principle could lead to rapid clinical translation due to the safety of GABA consumption.